2. The head of a pin can hold five hundred million rhinoviruses (cause of the common cold). One sneeze can generate an aerosol of enough cold viruses to infect thousands of people!

3. Antiviral chemotherapy Virus Structure and Replication Viruses are the smallest infective agent, effectively consisting of nucleic acid (DNA or RNA) enclosed in a protein coat. Viruses are intracellular parasites with no, or little, metabolic machinery of their own. They have to borrow the biochemistry of the host cell to succeed and grow (this is what makes selective antiviral therapy so difficult).

4. The virus attaches to specific receptors on the host cell surface which are normal membrane components. Usually ion channels, neurotransmitter receptors. The receptor/virus complex enters the cell by receptor-mediated endocytosis during which the virus coat may be removed. The nucleic acid of the virus then hijacks the cellular machinery for replicating viral nucleic acids and proteins for the manufacture of new virus particles. Antiviral chemotherapy

5. The genome of DNA viruses enters the cell nucleus and uses host RNA polymerase to produce virus- specific proteins. After assembly of coat proteins around the viral DNA, complete virions are released by budding or after cell lyses. Generally, RNA virus replication occurs solely in the cytoplasm and doesn’t involve the cellular nucleus. (influenza are an exception since they have a requirement for active cellular transcription). Antiviral chemotherapy

7. Treatment of Herpesviruses Varicella-zoster, Cytomegalavirus, Herpes simplex

8. Anti-metabolites “False” DNA building blocks or nucleosides. A nucleoside consists of a nucleobase and the sugar deoxyribose. In antimetabolites, one of the components is defective. In the body, the abnormal nucleosides undergo bioactivation by attachment of three phosphate residues Acyclovir has both specificity of the highest degree and optimal tolerability, because it undergoes bioactivation only in infected cells, where it preferentially inhibits viral DNA synthesis.

10. Acyclovir A virally coded thymidine kinase (specific to H.simplex and varicella-zoster virus) performs the initial phosphorylation step; the remaining two phosphate residues are attached by cellular kinases. Acyclovir triphosphate inhibits viral DNA polymerase resulting in chain termination. It is 30-fold more potent against the virus enzyme than the host enzyme. Acyclovir is active against herpes simplex and varicellar- zoster virus. It is rapidly broken down in cells, is orally active and is relatively non-toxic systemically.

11. Acyclovir and Valacyclovir (pro-drug, better availability) A Guanine analogue with antiviral for Herpes group only AcyclovirAcycloGMPAcycloGTP Thymidine kinase Cellular kinases Viral 200x affinity of mammalian 1.Inhibits viral DNA polymerase selectively 2.Incorporated into DNA and terminates synthesis Resistance: 1. ↓ activity of thymidine kinase 2. altered DNA polymerase

13. Acyclovir is used to treat: Herpes simplex infections (genital herpes, and herpes encephalitis). Chickenpox in immuno-compromised patients. Prophylactically in patients treated with immunosuppressant drugs or radiotherapy who are in danger of infection by reactivation of latent virus. Prophylactically in patients with frequent recurrences of genital herpes. Acyclovir

14. Oral acyclovir has multiple uses. In first episodes of genital herpes, oral acyclovir shortens the duration of symptoms by approximately 2 days, the time to lesion healing by 4 days, and the duration of viral shedding by 7 days. In recurrent genital herpes, the time course is shortened by 1–2 days. Oral acyclovir is only modestly beneficial in recurrent herpes labialis. Topical acyclovir cream is substantially less effective than oral therapy for primary HSV infection. It is of no benefit in treating recurrent genital herpes.

15. Acyclovir Common adverse drug reactions are nausea, vomiting, diarrhea and headache. Additional common adverse effects, when acyclovir is administered IV, include : Renal insufficiency and neurologic toxicity However, incommon with adequate hydration and avoidance of rapid infusion rate.

16. Docosanol Docosanol is a saturated 22-carbon aliphatic alcohol that inhibits fusion between the plasma membrane and the HSV envelope, thereby preventing viral entry into cells and subsequent viral replication. Topical docosanol 10% cream is available without a prescription; application site reactions occur in approximately 2% of patients. When applied within 12 hours of the onset of prodromal symptoms, five times daily, median healing time was shortened by 18 hours compared with placebo in recurrent orolabial herpes.

17. Ganciclovir Mechanism like Acyclovir Active against all Herpes viruses including CMV (100 time than acyclovir) Low oral bioavailability given I.V. Most common adverse effect: bone marrow suppression (leukopenia 40%, thrombocytopenia 20%) and CNS effects (headache, behavioral, psychosis, coma, convulsions). 1/3 of patients have to stop because of adverse effects Drug of choice for CMV infections: retinitis, pneumonia, colitis.

18. Foscarnet An inorganic pyrophosphate analog Active against Herpes (I, II, Varicella, CMV), including those resistant to Acyclovir and Ganciclovir. Direct inhibition of DNA polymerase and Reverse Transcriptase Nephrotoxicity (25%) most common side effect Use: (1) CMV retinitis and other CMV infections instead of ganciclovir (2) H. simplex resistant to Acyclovir. (3) HIV.

20. Vidarabine Inhibits virally induced DNA polymerase more strongly than it does the endogenous enzyme. Vidarabine is a chain terminator and is active against herpes simplex, varicella zoster, and vaccinia are especially sensitive. Its use is now limited to topical treatment of severe herpes simplex infection. Before the introduction of the better tolerated acyclovir, vidarabine played a major part in the treatment of herpes simplex encephalitis. Its clinically used in treatment of immunocompromised patients with herpetic and vaccinia keratitis and in keratoconjunctivitis.

21. Treatment of respiratory virus infection Influenza A & B Respiratory suncytial virus (RSV)

22. Attachment Inhibitors The primary antiviral mechanism of Amantadine and Rimantadine is to block the viral membrane matrix protein, which function as an ion channel that is required for the fusion of the viral membrane with the cell membrane. Their clinical use is limited to Influenza A infection. They are very effective in preventing infection if the treatment is begun at the time of-or prior to- exposure to the virus.

24. Attachment Inhibitors Side effects of Amantadine are mainly associated with the CNS, such as ataxia and dizziness. While Rimantadine produce little CNS effect because it does not penetrate the blood brain barrier. Both should be used with caution in pregnant and nursing women.

25. 25 Oseltamivir and Zanamavir Mechanism of action Viral neuraminidase catalyzes cleavage of terminal sialic acid residues attached to glycoproteins and glycolipids, a process necessary for release of virus from host cell surfaces. Neuraminidase inhibitors thus prevent release of virions from infected cell Neuroaminidase inhibitors

26. Administration of neuraminidase inhibitors is a treatment that limits the severity and spread of viral infections. Neuraminidase inhibitors are useful for combating influenza infection: zanamivir, administered by inhalation; oseltamivir, administered orally. Toxicities – Exacerbation of reactive airway disease by zanamavir – Nausea and vomiting for oseltamivir

27. oseltamivir Early administration is crucial because replication of influenza virus peaks at 24–72 hours after the onset of illness. When a 5-day course of therapy is initiated within 36–48 hours after the onset of symptoms, the duration of illness is decreased by 1–2 days compared with those on placebo, severity is diminished, and the incidence of secondary complications in children and adults decreases. Once-daily prophylaxis is 70–90% effective in preventing disease after exposure.

28. Ribavirin It is an antimetabolite that inhibits influenza RNA polymerase non-competitively in vitro but poorly in vivo. An aerosol form is used against RSV (respiratory syncytial virus) and the drug is used intravenously against Lassa fever. Adverse reactions includes: Anemia due to hemolysis and bone marrow suppression

29. Antiretroviral agents

30. HIV Life Cycle Step 1: Fusion Step 2: Transcription reverse transcriptase Step 3: Integration Step 4: Cleavage Step 5: Packaging and Budding HIV

31. Azidothymidine (Zidovudin(AZT)) It is a potent antagonist of reverse transcriptase, It is a chain terminator. Cellular enzyme phosphorylate AZT to the triphosphate form which inhibits RT and causes chain termination It is widely use in the treatment of AIDS (The only clinical use). AZT is toxic to bone marrow, for example, it cause severe anaemia and leukopenia In patient receiving high dose. Headache is also common

32. Didanosine (Dideoxyinosine) Didanosine act as chain terminators and inhibitors of reverse transcriptase because they lack a hydroxyl group. is phosphorylated to the active metabolite of dideoxyadenosine triphosphate It is used in the treatment of AIDS (second drug approved to treat HIV-1 infection). They are given orally, and their main toxicities are pancreatitis, peripheral neuropathy, GI disturbance, bone marrow depression.

33. 33 (1) bind to viral RT, inducing conformational changes that result in enzyme inhibition (2) Combination therapy with AZT (resistant mutants rapidly emerge, little use in monotherapy) (3) Resistance mutations will be at different sites Non-nucleoside Non-competitive RT inhibitors

34. 34 Nevirapine Approved for AIDS patients, Good blocker of mother to child transmission (perinatal - breast feeding) Single dose at delivery reduced HIV transmission by 50% Single dose to baby by 72 hours Non-nucleoside Non-competitive RT inhibitors NNRTI’s: Adverse Effects RASH!! CNS effects (e.g. sedation, insomnia, vivid dreams, dizziness, confusion, feeling of “disengagement”)

35. Rash Rash, occurs in up to 20% of patients, usually in the first 4–6 weeks of therapy. Although typically mild and self-limited, rash is dose- limiting in about 7% of patients. Women appear to have an increased incidence of rash. When initiating therapy, gradual dose escalation over 14 days is recommended to decrease the incidence of rash.

36. Protease Inhibitors HIV Protease Inhibitors; have significantly alter the course of the HIV disease. All are reversible inhibitors of HIV Protease-the viral enzyme responsible for cleavage of viral polyprotein into number of essential enzymes (reverse transcription, polymerase). Examples are : Saquinavir, and Ritonavir. They are orally active, side effects include GI disturbances and hyperglycemia, interact with cytochrome P450. buffalo hump

37. 37 GAGIntegrasePolymeraseProtease GAG/POL polyprotein Anti-Viral Chemotherapy Retrovirus --- HIV

38. Anti-Viral Chemotherapy 38 GAGIntegrasePolymerase Protease folds and cuts itself free

39. 39 GAGIntegrasePolymerase Protease cuts at a site between the integrase and polymerase Anti-Viral Chemotherapy

40. 40 GAGIntegrase polymerase Anti-Viral Chemotherapy

42. New targets Enfuvirtide is Peptides derived from gp41 can inhibit infection, probably by blocking the interaction of gp41 with cell membrane proteins during fusion. Raltegravir (Integrase Inhibitor) targets integrase, an HIV enzyme that integrates the viral genetic material into human chromosomes, a critical step in the pathogenesis of HIV. Maraviroc It blocks the interaction between chemokine receptor CCR5 and HIV gp120.

43. (HAART) Highly active anti-retroviral therapies Combination therapies (triple drug cocktail, HAART) are very effective and can reduce viral load in the patient below detectable levels implying that HIV replication has ceased. examples (1) NNRTI–Based Regimens (1-NNRTI + 2NRTIs) (2) PI-Based Regimens (1 or 2 PIs + 2 NRTIs) The trouble with all of these complicated drug regimens is compliance. The components of HAART must be taken at different times. Non-compliance with protease inhibitor therapy is of serious concern as the new virus that emerges is resistant to the inhibitor being taken and also resistant to other protease inhibitors.

44. Anti-Hepatitis B Virus Agents Figure 2. Timeline of evolution of HBV therapies, United States.

45. Interferons Interferon Alfa Endogenous proteins induce host cell enzymes that inhibit viral RNA translation and cause degradation of viral mRNA and tRNA. Bind to membrane receptors on cell surface, May also inhibit viral penetration, uncoating, mRNA synthesis, and translation, and virion assembly and release. Pegylated interferon Alfa A linear or branced polyethylene gylcol (PEG) moiety is attached covalently to interferon Increased half-life and steady drug concentrations

47. Interferons a limited treatment course (ie, only 1 year of therapy), lack of resistance development. Disadvantages include a high rate of treatment-related adverse events. flu-like symptoms: increased body temperature, feeling ill, fatigue, headache, muscle pain.

48. Anti-Hepatitis C Virus Agents Approved – Interferon-alpha (pegylated) – Ribavirin In development – Protease inhibitors – Polymerase inhibitors

49. In pregnancy, a regimen of oral zidovudine beginning between 14 and 34 weeks of gestation, intravenous zidovudine during labor, and zidovudine syrup to the neonate from birth through 6 weeks of age has been shown to reduce the rate of vertical (mother- to-newborn) transmission of HIV by up to 23%.